US11644462B2 - Targeted near-infrared imaging by metal-organic frameworks - Google Patents
Targeted near-infrared imaging by metal-organic frameworks Download PDFInfo
- Publication number
- US11644462B2 US11644462B2 US17/243,417 US202117243417A US11644462B2 US 11644462 B2 US11644462 B2 US 11644462B2 US 202117243417 A US202117243417 A US 202117243417A US 11644462 B2 US11644462 B2 US 11644462B2
- Authority
- US
- United States
- Prior art keywords
- metal
- organic framework
- linker
- biological molecule
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000012621 metal-organic framework Substances 0.000 title claims abstract description 88
- 238000003333 near-infrared imaging Methods 0.000 title claims description 9
- 230000021615 conjugation Effects 0.000 claims abstract description 34
- 150000001718 carbodiimides Chemical class 0.000 claims abstract description 16
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 29
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 21
- 229910052751 metal Inorganic materials 0.000 claims description 19
- 239000002184 metal Substances 0.000 claims description 19
- 125000003277 amino group Chemical group 0.000 claims description 18
- 229910052761 rare earth metal Inorganic materials 0.000 claims description 18
- -1 rare earth metal ions Chemical class 0.000 claims description 17
- 108010090804 Streptavidin Proteins 0.000 claims description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 7
- 150000002910 rare earth metals Chemical class 0.000 claims description 6
- 230000001268 conjugating effect Effects 0.000 claims description 5
- GPNNOCMCNFXRAO-UHFFFAOYSA-N 2-aminoterephthalic acid Chemical compound NC1=CC(C(O)=O)=CC=C1C(O)=O GPNNOCMCNFXRAO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052684 Cerium Inorganic materials 0.000 claims description 3
- 229910052692 Dysprosium Inorganic materials 0.000 claims description 3
- 229910052691 Erbium Inorganic materials 0.000 claims description 3
- 229910052693 Europium Inorganic materials 0.000 claims description 3
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 3
- 229910052689 Holmium Inorganic materials 0.000 claims description 3
- 229910052779 Neodymium Inorganic materials 0.000 claims description 3
- 229910052777 Praseodymium Inorganic materials 0.000 claims description 3
- 229910052772 Samarium Inorganic materials 0.000 claims description 3
- 229910052771 Terbium Inorganic materials 0.000 claims description 3
- 229910052775 Thulium Inorganic materials 0.000 claims description 3
- 229910052769 Ytterbium Inorganic materials 0.000 claims description 3
- MNWFXJYAOYHMED-UHFFFAOYSA-N hexane carboxylic acid Natural products CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 150000000000 tetracarboxylic acids Chemical class 0.000 claims description 3
- CNHYKKNIIGEXAY-UHFFFAOYSA-N thiolan-2-imine Chemical compound N=C1CCCS1 CNHYKKNIIGEXAY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 2
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 claims description 2
- 150000002394 hexacarboxylic acid derivatives Chemical class 0.000 claims 1
- 150000003627 tricarboxylic acid derivatives Chemical class 0.000 claims 1
- 102000004169 proteins and genes Human genes 0.000 abstract description 24
- 108090000623 proteins and genes Proteins 0.000 abstract description 24
- 210000004027 cell Anatomy 0.000 abstract description 23
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 abstract description 18
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 abstract description 18
- 238000003384 imaging method Methods 0.000 abstract description 15
- 239000000126 substance Substances 0.000 abstract description 13
- 230000008685 targeting Effects 0.000 abstract description 9
- 210000002919 epithelial cell Anatomy 0.000 abstract description 8
- 108090000790 Enzymes Proteins 0.000 abstract description 5
- 102000004190 Enzymes Human genes 0.000 abstract description 5
- 150000001412 amines Chemical class 0.000 abstract description 5
- ATGUDZODTABURZ-UHFFFAOYSA-N thiolan-2-ylideneazanium;chloride Chemical compound Cl.N=C1CCCS1 ATGUDZODTABURZ-UHFFFAOYSA-N 0.000 abstract description 5
- 238000004624 confocal microscopy Methods 0.000 abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 2
- 238000004132 cross linking Methods 0.000 abstract description 2
- 239000002245 particle Substances 0.000 description 65
- 108010087904 neutravidin Proteins 0.000 description 28
- 235000018102 proteins Nutrition 0.000 description 23
- 239000000463 material Substances 0.000 description 21
- 238000005119 centrifugation Methods 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 13
- 239000002953 phosphate buffered saline Substances 0.000 description 13
- 230000003833 cell viability Effects 0.000 description 12
- 150000003141 primary amines Chemical group 0.000 description 11
- 230000003993 interaction Effects 0.000 description 8
- 210000002540 macrophage Anatomy 0.000 description 8
- OYFRNYNHAZOYNF-UHFFFAOYSA-N 2,5-dihydroxyterephthalic acid Chemical compound OC(=O)C1=CC(O)=C(C(O)=O)C=C1O OYFRNYNHAZOYNF-UHFFFAOYSA-N 0.000 description 7
- 108090001008 Avidin Proteins 0.000 description 7
- 230000005284 excitation Effects 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- 230000003595 spectral effect Effects 0.000 description 6
- 238000006177 thiolation reaction Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- RPENMORRBUTCPR-UHFFFAOYSA-M sodium;1-hydroxy-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].ON1C(=O)CC(S([O-])(=O)=O)C1=O RPENMORRBUTCPR-UHFFFAOYSA-M 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 4
- 238000012984 biological imaging Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000000295 emission spectrum Methods 0.000 description 4
- 238000000386 microscopy Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000005424 photoluminescence Methods 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 238000012790 confirmation Methods 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 238000012634 optical imaging Methods 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- RTSZQXSYCGBHMO-UHFFFAOYSA-N 1,2,4-trichloro-3-prop-1-ynoxybenzene Chemical compound CC#COC1=C(Cl)C=CC(Cl)=C1Cl RTSZQXSYCGBHMO-UHFFFAOYSA-N 0.000 description 2
- GVJXGCIPWAVXJP-UHFFFAOYSA-N 2,5-dioxo-1-oxoniopyrrolidine-3-sulfonate Chemical compound ON1C(=O)CC(S(O)(=O)=O)C1=O GVJXGCIPWAVXJP-UHFFFAOYSA-N 0.000 description 2
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KPKZJLCSROULON-QKGLWVMZSA-N Phalloidin Chemical compound N1C(=O)[C@@H]([C@@H](O)C)NC(=O)[C@H](C)NC(=O)[C@H](C[C@@](C)(O)CO)NC(=O)[C@H](C2)NC(=O)[C@H](C)NC(=O)[C@@H]3C[C@H](O)CN3C(=O)[C@@H]1CSC1=C2C2=CC=CC=C2N1 KPKZJLCSROULON-QKGLWVMZSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000003466 anti-cipated effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 230000008614 cellular interaction Effects 0.000 description 2
- 238000002591 computed tomography Methods 0.000 description 2
- 238000002059 diagnostic imaging Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 150000002395 hexacarboxylic acids Chemical class 0.000 description 2
- 239000012216 imaging agent Substances 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 108700041430 link Proteins 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000002924 oxiranes Chemical class 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000002731 protein assay Methods 0.000 description 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 2
- 238000006862 quantum yield reaction Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000003325 tomography Methods 0.000 description 2
- 150000003628 tricarboxylic acids Chemical class 0.000 description 2
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- NEQFBGHQPUXOFH-UHFFFAOYSA-N 4-(4-carboxyphenyl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=C(C(O)=O)C=C1 NEQFBGHQPUXOFH-UHFFFAOYSA-N 0.000 description 1
- SBBQDUFLZGOASY-OWOJBTEDSA-N 4-[(e)-2-(4-carboxyphenyl)ethenyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1\C=C\C1=CC=C(C(O)=O)C=C1 SBBQDUFLZGOASY-OWOJBTEDSA-N 0.000 description 1
- SRTQKANXPMBQCX-UHFFFAOYSA-N 4-[2,4,5-tris(4-carboxyphenyl)phenyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC(C=2C=CC(=CC=2)C(O)=O)=C(C=2C=CC(=CC=2)C(O)=O)C=C1C1=CC=C(C(O)=O)C=C1 SRTQKANXPMBQCX-UHFFFAOYSA-N 0.000 description 1
- LSIRFWJQXQJPKC-UHFFFAOYSA-N 4-[2-(4-carboxy-2-nitrophenyl)ethenyl]-3-nitrobenzoic acid Chemical compound [O-][N+](=O)C1=CC(C(=O)O)=CC=C1C=CC1=CC=C(C(O)=O)C=C1[N+]([O-])=O LSIRFWJQXQJPKC-UHFFFAOYSA-N 0.000 description 1
- SATWKVZGMWCXOJ-UHFFFAOYSA-N 4-[3,5-bis(4-carboxyphenyl)phenyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC(C=2C=CC(=CC=2)C(O)=O)=CC(C=2C=CC(=CC=2)C(O)=O)=C1 SATWKVZGMWCXOJ-UHFFFAOYSA-N 0.000 description 1
- LLLSQRNDRHARFZ-UHFFFAOYSA-N 4-[4-[2,3,4,5,6-pentakis[4-(4-carboxyphenyl)phenyl]phenyl]phenyl]benzoic acid Chemical compound OC(=O)c1ccc(cc1)-c1ccc(cc1)-c1c(-c2ccc(cc2)-c2ccc(cc2)C(O)=O)c(-c2ccc(cc2)-c2ccc(cc2)C(O)=O)c(-c2ccc(cc2)-c2ccc(cc2)C(O)=O)c(-c2ccc(cc2)-c2ccc(cc2)C(O)=O)c1-c1ccc(cc1)-c1ccc(cc1)C(O)=O LLLSQRNDRHARFZ-UHFFFAOYSA-N 0.000 description 1
- PEQRGMPXYDIZSX-UHFFFAOYSA-N 4-[4-[3,5-bis[4-(4-carboxyphenyl)phenyl]phenyl]phenyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=C(C=2C=C(C=C(C=2)C=2C=CC(=CC=2)C=2C=CC(=CC=2)C(O)=O)C=2C=CC(=CC=2)C=2C=CC(=CC=2)C(O)=O)C=C1 PEQRGMPXYDIZSX-UHFFFAOYSA-N 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 108090000197 Clusterin Proteins 0.000 description 1
- 102000003780 Clusterin Human genes 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 description 1
- 101710091977 Hydrophobin Proteins 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 108091093037 Peptide nucleic acid Proteins 0.000 description 1
- 108010009711 Phalloidine Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000004791 biological behavior Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- ARRNBPCNZJXHRJ-UHFFFAOYSA-M hydron;tetrabutylazanium;phosphate Chemical compound OP(O)([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC ARRNBPCNZJXHRJ-UHFFFAOYSA-M 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 1
- 229960004657 indocyanine green Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000013112 mixed metal metal-organic framework Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 239000012120 mounting media Substances 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000013630 prepared media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000006557 surface reaction Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- JDFUJAMTCCQARF-UHFFFAOYSA-N tatb Chemical compound NC1=C([N+]([O-])=O)C(N)=C([N+]([O-])=O)C(N)=C1[N+]([O-])=O JDFUJAMTCCQARF-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
- 238000001429 visible spectrum Methods 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0065—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0058—Antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/02—Use of particular materials as binders, particle coatings or suspension media therefor
- C09K11/025—Use of particular materials as binders, particle coatings or suspension media therefor non-luminescent particle coatings or suspension media
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/544—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being organic
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0213—Complexes without C-metal linkages
- B01J2531/0216—Bi- or polynuclear complexes, i.e. comprising two or more metal coordination centres, without metal-metal bonds, e.g. Cp(Lx)Zr-imidazole-Zr(Lx)Cp
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/30—Complexes comprising metals of Group III (IIIA or IIIB) as the central metal
- B01J2531/38—Lanthanides other than lanthanum
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/1691—Coordination polymers, e.g. metal-organic frameworks [MOF]
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
- B01J31/223—At least two oxygen atoms present in one at least bidentate or bridging ligand
- B01J31/2239—Bridging ligands, e.g. OAc in Cr2(OAc)4, Pt4(OAc)8 or dicarboxylate ligands
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
- B01J31/2243—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/18—Metal complexes
- C09K2211/182—Metal complexes of the rare earth metals, i.e. Sc, Y or lanthanide
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2458/00—Labels used in chemical analysis of biological material
- G01N2458/40—Rare earth chelates
Definitions
- the present invention relates to biomedical imaging and, in particular, to targeted near-infrared imaging of biological materials by metal-organic frameworks.
- MOFs metal-organic frameworks
- NIR imaging in the first window (NIR-I, 700-900 nm) has been successful in clinical use but is limited by poor tissue penetration and a high degree of light scattering, leading to limited spatial resolution and restricted imaging uses.
- NIR-II second NIR window imaging
- MOFs have been designed for imaging within the NIR windows utilizing Yb or incorporation of the NIR dye, indocyanine green. See K. Lu et al., Adv. Mater. 30, 1707634 (2016); W. Cai et al., ACS Appl. Mater. Interfaces 9, 2040 (2017); and A. Foucault-Collet et al., Proc. Natl. Acad. Sci. 110, 17199 (2013).
- MOF-based photoluminescence can be achieved through incorporation of fluorescent linkers, encapsulation of fluorescent dyes or via intrinsic emission properties of the metals. See S. E.
- MOF luminescent imaging can also be done in vivo in rodent models, allowing tracking of biodistribution of MOF nanocarriers. See R. Nishiyabu et al., J. Am. Chem. Soc. 131, 2151 (2009); and X. Gao et al., Dalton Trans. 46, 13686 (2017). Additionally, many in vivo imaging modalities, such as MRI, lack detailed spatial resolution necessary to determine the specific cellular interaction in tissues. As the specific cellular interaction, such as cell type, can be highly important for diagnostic imaging and therapeutic delivery, mixed metal MOFs with a visible optical signal as well as MRI signature have been created. See X.
- the present invention is directed to a near-infrared imaging metal-organic framework, comprising a plurality of metal clusters, each cluster comprising one or more rare earth metal ions, and a plurality of carboxylic acid-based linkers coordinating with the plurality of metal clusters, wherein the carboxylic acid-based linkers further comprise one or more amine groups within the linker.
- the rare earth metal can comprise Nd, Yb, Eu, Y, Ce, Pr, Sm, Gd, Tb, Dy, Ho, Er, Tm, or mixtures thereof.
- the at least one metal cluster can comprise a first rare earth metal ion and a second rare earth metal ion that is different from the first rare earth metal ion.
- the carboxylic acid-based linker can comprise an amino-containing di-, tri-, tetra-, or hexacarboxylic acid.
- a large variety of biologically relevant molecules can be conjugated to the MOF including, but not limited to, peptides, proteins (e.g., avidin, CD47, fibrinogen, bovine serum albumin, clusterin, hydrophobin, T-cell receptors, antibodies, and enzymes), nucleic acids (e.g., ribonucleic acids, deoxyribonucleic acids, and peptide nucleic acids), nanobodies, and polymers that can alter biological behavior (e.g., polyethylene glycol, chitosan, and poly(D,L-lactic-co-glycolic acid)).
- the present invention further comprises a method for targeted near-infrared imaging, comprising providing a metal-organic framework and conjugating a biological molecule to the metal-organic framework via an amine group within the linker.
- the amino functional group enables biological based conjugation in a MOF with predetermined features.
- antibodies were conjugated to the available amino group utilizing a common conjugation method, carbodiimide chemistry, and a more specialized chemistry utilizing sulfhydryl chemistry via Traut's reagent. This latter method of chemical conjugation has significant advantages in the realm of biological conjugations due to the ability to utilize cysteine residues within proteins or add these residues to the end of the protein.
- an epithelial cell adhesion molecule (EpCAM) antibody targeted MOFs to bind to their target cells and be imaged via confocal microscopy was demonstrated.
- the targeting capability can be expanded to additional targeting moieties.
- Other biologically relevant proteins can also be targeted to further alter the MOF interaction with cells.
- This family of RE-containing MOFs with amino functional groups can provide combined visible/NIR emitting MOFs to expand the targeting capabilities into the visible and NIR-I and NIR-II imaging windows.
- FIG. 1 A shows the 2-aminoterephthalic acid linker molecule.
- FIG. 1 B illustrates a representative targeted Eu hexanuclear cluster.
- FIG. 2 is a graph of powder X-ray diffraction (XRD) patterns of calculated EuDOBDC as compared to that experimentally measured on an Eu-2-amino-BDC sample.
- XRD powder X-ray diffraction
- FIG. 3 A is a representative scanning electron microscope (SEM) image for the Eu-2-amino-BDC material.
- FIG. 3 B is a representative transmission electron microscope (TEM) image for the Eu-2-amino-BDC material.
- FIG. 4 is a graph of nitrogen adsorption isotherm measured at 77K on the Eu-2-amino-BDC sample.
- FIG. 5 is a graph of photoluminescence excitation (PLE) and emission (PL) spectra for the Eu-2-amino-BDC sample; the emission spectra are offset for clarity.
- FIG. 6 A is a graph of cell viability of the A549 human lung epithelial cell line after 24 and 48 h exposure to Eu-2-amino particles.
- FIG. 6 B is a graph of cell viability for the RAW 264.7 mouse macrophage cell line after 24 and 48 h exposure to Eu-2-amino particles.
- FIG. 7 illustrates a method to conjugate a primary amine group on a MOF linker with a carboxylic acid group on a biological molecule using carbodiimide chemistry.
- FIG. 8 illustrates a method to conjugate a MOF to a biological molecule using thiolation chemistry.
- FIG. 9 illustrates a method to bind biotinylated molecules to a streptavidin molecule attached to a MOF.
- FIGS. 10 A and 10 B show confirmation of NeutrAvidin and EpCAM antibody conjugation to the Eu-2-amino-BDC particles using the carbodiimide chemistry (method 1) and thiolation chemistry (method 2).
- FIG. 10 A is a graph showing NanoOrange protein quantitation to confirm the conjugation of the NeutrAvidin protein and the EpCAM antibody to the Eu-2-amino-BDC particles.
- FIG. 10 B is a graph showing fluorescently labeled secondary antibody to the EpCAM antibody to confirm the conjugation of EpCAM antibody to the NeutrAvidin conjugated Eu-2-amino-BDC particles.
- FIG. 11 illustrates MOF interaction with A549 cells.
- the EpCAM antibody targeted Eu-2-amino-BDC particles showed significant interactions with the EpCAM bearing A549 cells, while the untargeted Eu-2-amino-BDC particles showed minimal interaction after 4 hours.
- the cell cytoskeleton is visualized using Alexa 488 labeled phalloidin, the nucleus is visualized using DAPI and the Eu-2-amino-BDC particles are visualized using the particle's inherent photoluminescence. Images were collected at 63 ⁇ and the scale bars represent 10 ⁇ m.
- MOFs incorporate single metal ions or clusters of metal ions connected by organic linkers that can efficiently sensitize luminescent metal ions.
- a multifunctional biocompatible MOF materials platform based on rare earth metal ions has been recently reported. See D. F. Sava Gallis et al., ACS Appl. Mater. Interfaces 9, 22268 (2017). These MOF materials are amenable for bioimaging applications, in the visible range and in both NIR windows. Subsequent studies have focused on tuning of particle size with emphasis on increasing quantum yield in these materials systems. These materials have produced the highest quantum yield observed in NIR-emitting MOFs to date. See D. F. Sava Gallis et al., CrystEngComm 20, 5919 (2016).
- Primary amine groups represent one of the most versatile chemical moieties for conjugation to biologically relevant molecules, such as fluorescent labels, nucleic acids, peptides and proteins (including antibodies and enzymes), which can have limited or no stability in non-aqueous, low pH, high pH, or high temperature reaction environments. See R. Kazlauskas, R., Chem. Soc. Rev. 47, 9026 (2016); and Y. Le Basle et al., J. Pharm. Sci. 109, 169 (2020).
- primary amines can form chemical bonds with a wide variety of synthetic chemical groups including isothiocyanates, isocyanates, acyl azides, NHS esters, sulfonyl chlorides, aldehydes, glyoxals, epoxides, oxiranes, carbonates, aryl halides, imidoesters, carbodiimides, anhydrides, and fluorophenyl esters.
- the present invention is directed to a targeted imaging agent, as facilitated by both the facile chemistry of the MOFs, in general, and the highly tunable nature of this materials platform, in particular.
- a targeted imaging agent as facilitated by both the facile chemistry of the MOFs, in general, and the highly tunable nature of this materials platform, in particular.
- the ability to chemically bind antibodies to MOFs is highly relevant for use in a wide variety of assays and as novel targeted imaging agents for biological/medical imaging. See S. Wang et al., Adv. Mater. 30, 1800202 (2016).
- the present invention is further directed to MOFs that comprise rare earth metals that form metal clusters that are coordinated with carboxylic acid-based linkers, wherein the carboxylic acid-based linkers comprise one or more amine groups.
- rare earth metals that can be used include Nd, Yb, Eu, Y, Ce, Pr, Sm, Gd, Tb, Dy, Ho, Er, and Tm. These rare earth metals will result in distinct emission properties.
- a variety of carboxylic acid-based linkers can be used to connect the metal clusters, including amino analogs of di-, tri-, tetra-, and hexacarboxylic acids.
- Exemplary linear dicarboxylic acid linkers include 4,4′-stilbenedicarboxylic acid, 2,2′-dinitro-4,4′-stilbenedicarboxylic acid, 2′2-diamino-4,4′-stilbenedicarboxylic acid, 2,5-dihydroxyterephthalic acid (DOBDC), 4,4′-biphenyl dicarboxylic acid, and 1,4-napthalene dicarboxylic acid.
- DOBDC 2,5-dihydroxyterephthalic acid
- DOBDC 4,4′-biphenyl dicarboxylic acid
- 1,4-napthalene dicarboxylic acid 1,4-napthalene dicarboxylic acid.
- Exemplary tricarboxylic acid linkers include 1,3,5-tris(4-carboxyphenyl)benzene (BTB), 4,4′,4′′-5-triazine-2,4,6-triyl-tribenzoic acid (TATB), and 1,3,5-tris(4′-carboxy[1,1′-biphenyl]-4-yl)benzene (TCBB).
- Exemplary tetracarboxylic acid linkers include 1,2,4,5-tetrakis(4-carboxyphenyl)benzene (TCPB) and 1,3,6,8-tetra(4/carboxyphenyl)pyrene (TBAP).
- An exemplary hexacarboxylic acid linker includes 1,2,3,4,5,6-hexakis(4′-carboxylato(1,1′-biphenyl)-4-yl)benzene.
- a linear linker such as DOBDC, will likely form hexanuclear metal clusters.
- Tetratopic linkers such as TCPB, will likely form nonanuclear metal clusters. See U.S. application Ser. No. 15/994,904, filed May 31, 2018, which is incorporated herein by reference.
- the invention is further directed to rare-earth MOFs (RE-MOFs) comprising analogs of carboxylic acid-based linkers that further comprise one or more primary amines within the linker that are available for conjugation to biologically relevant molecules.
- RE-MOFs rare-earth MOFs
- 2-aminoterephthalic acid (2-amino-BDC) was used to synthesize the Eu-based analog of the originally reported EuDOBDC material based on a 2,5-dihydroxyterephthalic acid (DOBDC) linker. See D. F. Sava Gallis et al., ACS Appl. Mater. Interfaces 9, 22268 (2017).
- the exemplary 2-aminoterephthalic acid molecule is shown in FIG. 1 A .
- FIG. 1 B A predetermined/targeted hexanuclear metal cluster of the exemplary Eu-2-amino-BDC MOF is depicted in FIG. 1 B , showing carboxylate groups of the 2-amino-BDC linker molecules bridging the Eu atoms of the metal cluster.
- the synthesis of the Eu-2-amino-BDC material was performed using a microwave-assisted approach.
- a reaction mixture containing EuCl 3 .6H 2 O (0.0172 g, 0.047 mmol), 2-aminoterephthalic acid (0.0124 g, 0.068 mmol), 2-fluorobenzoic acid (2-FBA, 0.205 g, 1.463 mmol), and N,N′-dimethylformamide (DMF, 2 mL) was placed in a 10 mL microwave vial with a stir bar and was heated to 175° C. for 40 minutes with a 15s pre-mix. The reaction was then washed 3 ⁇ in DMF followed by 3 ⁇ in ethanol.
- FIG. 3 A reveals the relative uniform particles size in the Eu-2-amino-BDC material, as characterized by SEM microscopy. Further, the TEM image in FIG. 3 B shows the representative polyhedral morphology of an individual particle.
- the photoluminescent properties of the Eu-2-amino-BDC MOF were examined to confirm utility for biological imaging, as shown in FIG. 5 .
- Prior research has demonstrated that the originally reported EuDOBDC material displays broad excitation below 425 nm.
- the Eu-2-amino-BDC sample also showed the anticipated broad excitation below 425 nm, which is applicable to most laser microscopy systems for biological imaging which utilize Ar-UV lasers emitting at 351 nm and 364 nm, or 405 nm diode lasers.
- emission spectra were taken with excitation at 300 nm and 400 nm.
- the Eu-2-amino-BDC MOF also retained the narrowband emission peaks between 590 and 725 nm found previously with EuDOBDC and other Eu-containing MOFs. See X. Gao et al., Dalton Trans. 46, 13686 (2017); W. J. Rieter et al., J. Am. Chem. Soc. 128, 9024 (2006); and D. F. Sava Gallis et al., ACS Appl. Mater. Interfaces 9, 22268 (2017). Additionally, the emission spectra showed no change between excitation at 300 nm or 400 nm, similar to the observed lack of change in emission spectra of the EuDOBDC MOF with changing excitation.
- the spectral properties of the Eu-2-amino-BDC particles were assessed utilizing spectral scanning on a confocal microscope.
- the Eu-2-amino-BDC particles when deposited in cell mounting media and excited by a 405 nm laser, retained their spectral characteristics, showing narrow bands of emission between 575 and 710 nm. Additionally, a broad peak from 425 to 575 nm was observed which was attributed to the linker emission.
- laser power can be varied on a confocal microscope and higher laser power can be damaging to cells, the required laser power to visualize the Eu-2-amino-BDC particles was assessed.
- the Eu-2-amino-BDC particles were assessed for biocompatibility as measured by alterations in cell viability to mammalian cells.
- a human epithelial cell line (A549) and a mouse macrophage cell line (RAW 264.7) were chosen as epithelial cells are common targets for imaging studies and macrophages are involved in the clearance of injected particle materials. See G. Song et al., Curr. Rheumatol. Rev. 10, 22 (2014); and S. Park et al., Nat. Rev. Mater. 2, 17104 (2017).
- A549 were maintained in F-12K+10% fetal bovine serum (FBS, by volume) and RAW 264.7 cells were maintained in DMEM+4 mM L-glutamine+10% FBS (by volume).
- FBS fetal bovine serum
- DMEM+4 mM L-glutamine+10% FBS by volume
- 5,000 cells were plated per well in 100 ⁇ L media in 96 well plates and allowed to adhere overnight.
- Fresh media containing Eu-2-amino-BDC at varied concentration (0-500 ⁇ g/mL) were then prepared. Cell exposure was performed by removing media from the adherent cells, and then replacing it with freshly prepared media containing Eu-2-amino-BDC.
- Cells were incubated with Eu-2-amino-BDC MOF for 24 or 48 hours at standard cell culture conditions (37° C.
- cell viability was assessed using CellTiter-Glo 2.0 Assay (Promega) utilizing the standard protocol with luminescence measured by a BioTek Synergy Neo2 microplate reader. The cell viability was calculated as a percentage of mock treated sample. Cell viability measurements were done in quadruplicate and graphed as the average and standard deviation.
- both epithelial and macrophage cell viability was assessed after 24 and 48 h exposures at sample concentrations ranging from 1-500 ⁇ g/mL.
- both epithelial and macrophage cell lines there is a dose dependent increase in toxicity.
- the cell viability was greater than 75% at 200 ⁇ g/mL at 24 hours.
- the high cell viability at 24 h was previously seen with other RE-containing MOFs including Eu-containing MOFs. See D. F. Sava Gallis et al., ACS Appl. Mater. Interfaces 9, 22268 (2017).
- Carbodiimide chemistry links a primary amine group on the MOF linker with a carboxylic acid on a biological molecule (R) to form a carboxamide bond, as shown in FIG. 7 .
- R biological molecule
- water-soluble versions of this chemistry using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysulfosuccinimide (Sulfo-NHS) are the most common. Sulfo-NHS is not required, but it does increase the reaction efficiency. Importantly, no part of these chemicals is incorporated into the resulting carboxamide bond between the biological molecule and the MOF.
- carboxylic acid moieties on the MOF can link to primary amines within the biological molecule.
- An advantage of this chemistry is that carboxylic acids are very common in biology. Note that multiple biological molecules can be attached to a single MOF using this chemistry.
- a potential disadvantage is that, because of the ubiquity of such groups, it can be difficult to control the orientation of the conjugated molecule or protein.
- EDC and Sulfo-NHS were used to conjugate the streptavidin variant, NeutrAvidin, to the surface of the Eu-2-amino-BDC particles.
- carbodiimide chemistry (i) can utilize any primary amine and any carboxylic acid to create a linkage and (ii) proteins have many primary amines and carboxylic acids, the chemical conjugation can link proteins together which can create large agglomerations of proteins and particles.
- the reaction was allowed to proceed for 20 minutes at room temperature with mixing to activate the amines with NHS ester groups.
- the activated Eu-2-amino-BDC particles were then collected via centrifugation (10,000 RCF for 10 min) and resuspended in sterile filtered H 2 O. The centrifugation step was then repeated, and the activated particles were resuspended in 200 ⁇ L of sterile filtered H 2 O containing 0.12 mg of NeutrAvidin. Reaction was allowed to proceed for 2.5 h at room temperature with mixing to conjugate NeutrAvidin to the activated MOF surface.
- the avidin-conjugated Eu-2-amino-BDC particles were then collected via centrifugation (10,000 RCF for 10 min) and resuspended in PBS diluted 1:6 with sterile filtered H 2 O. After dilution with water, the concentration of salts was NaCl 25.86 mM, Na2HPO 4 0.49 mM and KH2PO 4 0.18 mM in the 1:6 PBS solution. The centrifugation step was then repeated, and the particles were resuspended in 120 ⁇ L PBS diluted 1:6 with sterile filtered H 2 O.
- Carbodiimide chemistry can also affect protein and antibody function through blocking or alteration of necessary sites on the protein.
- additional chemical opportunities become available, such as thiolation of the MOF with Traut's reagent to convert the amino group to a sulfhydryl group, as shown in FIG. 8 .
- Sulfhydryl groups can react with each other to form disulfide bonds, as shown in Scheme 1.
- This approach enables direct conjugation to a wide variety of peptides and proteins, including antibodies and enzymes.
- Thiol-modified DNA can also be attached using this method.
- An advantage of this method is that thiol group reactions allow more specificity in attaching the biological molecule to the MOF.
- the sulfhydryl group can be specifically added to proteins at controlled locations, making the conjugation sites much more specific than carbodiimide chemistry.
- the sulfhydryl group of the thiolated MOF can be reacted with a maleimide group on the biological molecule to create a stable thioether bond, as shown in Scheme 2.
- streptavidin and variants have a very high affinity for biotin and will react with any biotinylated substrate. Further, it is easy to get a wide variety of biological molecules biotinylated, including peptides, proteins (including antibodies and enzymes), nucleic acids (including PNA and DNA), and polymers.
- streptavidin SA
- SA can bind up to 4 biotinylated molecules (R), as shown in FIG. 9 .
- R biotinylated molecules
- the Traut's based chemistry was used to link maleimide-activated NeutrAvidin to the thiolated Eu-2-amino-BDC particles.
- the thiolated Eu-2-amino-BDC particles were then collected via centrifugation (10,000 RCF for 10 min) and resuspended in H 2 O. The centrifugation step was then repeated, and the thiolated particles were resuspended in 120 ⁇ L of sterile filtered H 2 O. The resuspended Eu-2-amino-BDC particles were added to an Eppendorf tube containing 0.10 mg of maleimide-activated NeutrAvidin. The reaction was allowed to proceed for 2.5 h at room temperature with mixing to conjugate the maleimide-activate NeutrAvidin to the thiolated particles.
- the avidin-conjugated Eu-2-amino-BDC particles were then collected via centrifugation (10,000 RCF for 10 min) and resuspended in PBS diluted 1:6 with sterile filtered H 2 O. Centrifugation step was then repeated, and the particles were resuspended in 120 ⁇ L PBS diluted 1:6 with sterile filtered H 2 O.
- 10 ⁇ g of biotinylated mouse anti-human EpCAM antibody (Invitrogen, clone 187) was added. The particles were incubated with the target antibody for 60 min at room temperature to bind the antibodies to the avidin-conjugated particles.
- the antibody-conjugated Eu-2-amino-BDC particles were then collected via centrifugation (10,000 RCF for 10 min) and resuspended in PBS diluted 1:6 with sterile filtered H 2 O. The centrifugation step was then repeated, and the antibody-conjugated particles were resuspended in PBS diluted 1:6 with sterile filtered H 2 O at 1 mg/mL and stored at 4° C. until use.
- NanoOrange protein quantitation was used to visualize the conjugation of the NeutrAvidin to the Eu-2-amino-BDC particles and the conjugation of the biotinylated EpCAM to the NeutrAvidin, as shown in FIG. 10 A .
- both conjugation chemistries there was a significant increase in protein presence between the NeutrAvidin conjugation step and the antibody conugation step.
- the increase in protein associated with the Eu-2-amino-BDC particles between the NeutrAvidin and antibody steps is indicative of antibody binding.
- each NeutrAvidin molecule can bind up to 4 biotinylated antibodies, so the mole ratio of NeutrAvidin to antibody was calculated from the protein assays to determine how many antibodies were bound to NuetrAvidin with each conjugation chemistry.
- the carbodiimide chemistry 1.01 biotinylated antibodies per NeutrAvidin compared to 2.78 antibodies per NeutrAvidin with the thiolation chemistry.
- fewer than the maximal antibodies were attached, likely due to steric hinderance of biotin binding sites due to attachment to a particle surface and density of NeutrAvidin on the surface.
- the carbodiimide chemistry appears to have caused a further decrease in available sites on NeutrAvidin for antibody attachment.
- 3D images were created using confocal microscopy. The 3D images were then sliced in the x, y, and z planes to allow clear visualization. With both conjugation methods, the 3D images demonstrated clear internalization into the A549 epithelial cells.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Cell Biology (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Analytical Chemistry (AREA)
- Food Science & Technology (AREA)
- Physics & Mathematics (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Materials Engineering (AREA)
- Inorganic Chemistry (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims (12)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/243,417 US11644462B2 (en) | 2017-06-19 | 2021-04-28 | Targeted near-infrared imaging by metal-organic frameworks |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762522006P | 2017-06-19 | 2017-06-19 | |
US15/994,904 US11007516B1 (en) | 2017-06-19 | 2018-05-31 | Tunable metal-organic framework compositions and methods thereof |
US17/243,417 US11644462B2 (en) | 2017-06-19 | 2021-04-28 | Targeted near-infrared imaging by metal-organic frameworks |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/994,904 Continuation-In-Part US11007516B1 (en) | 2017-06-19 | 2018-05-31 | Tunable metal-organic framework compositions and methods thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
US20210311041A1 US20210311041A1 (en) | 2021-10-07 |
US11644462B2 true US11644462B2 (en) | 2023-05-09 |
Family
ID=77921498
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/243,417 Active US11644462B2 (en) | 2017-06-19 | 2021-04-28 | Targeted near-infrared imaging by metal-organic frameworks |
Country Status (1)
Country | Link |
---|---|
US (1) | US11644462B2 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9920076B2 (en) | 2013-09-05 | 2018-03-20 | King Abdullah University Of Science And Technology | Tunable rare-earth fcu-metal-organic frameworks |
US11007516B1 (en) | 2017-06-19 | 2021-05-18 | National Technology & Engineering Solutions Of Sandia, Llc | Tunable metal-organic framework compositions and methods thereof |
-
2021
- 2021-04-28 US US17/243,417 patent/US11644462B2/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9920076B2 (en) | 2013-09-05 | 2018-03-20 | King Abdullah University Of Science And Technology | Tunable rare-earth fcu-metal-organic frameworks |
US11007516B1 (en) | 2017-06-19 | 2021-05-18 | National Technology & Engineering Solutions Of Sandia, Llc | Tunable metal-organic framework compositions and methods thereof |
Non-Patent Citations (30)
Also Published As
Publication number | Publication date |
---|---|
US20210311041A1 (en) | 2021-10-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Jiang et al. | Biocompatible Au@ Ag nanorod@ ZIF-8 core-shell nanoparticles for surface-enhanced Raman scattering imaging and drug delivery | |
Zhao et al. | Designing luminescent ruthenium prodrug for precise cancer therapy and rapid clinical diagnosis | |
Shamsipur et al. | Photoluminescence mechanisms of dual-emission fluorescent silver nanoclusters fabricated by human hemoglobin template: from oxidation-and aggregation-induced emission enhancement to targeted drug delivery and cell imaging | |
Tang et al. | Tunable ultrasmall visible-to-extended near-infrared emitting silver sulfide quantum dots for integrin-targeted cancer imaging | |
Butler et al. | Antibody targeted metal–organic frameworks for bioimaging applications | |
Na et al. | Multidentate catechol-based polyethylene glycol oligomers provide enhanced stability and biocompatibility to iron oxide nanoparticles | |
Bai et al. | A simple and general method for preparing antibody-PEG-PLGA sub-micron particles using electrospray technique: An in vitro study of targeted delivery of cisplatin to ovarian cancer cells | |
Zhou et al. | Low-toxic Mn-doped ZnSe@ ZnS quantum dots conjugated with nano-hydroxyapatite for cell imaging | |
Corsi et al. | HER2 expression in breast cancer cells is downregulated upon active targeting by antibody-engineered multifunctional nanoparticles in mice | |
Wang et al. | Peptide‐engineered fluorescent nanomaterials: Structure design, function tailoring, and biomedical applications | |
Bui et al. | Cationic two-photon lanthanide bioprobes able to accumulate in live cells | |
Park et al. | Cell-selective intracellular drug delivery using doxorubicin and α-helical peptides conjugated to gold nanoparticles | |
Maldiney et al. | Synthesis and functionalization of persistent luminescence nanoparticles with small molecules and evaluation of their targeting ability | |
KR20070088391A (en) | Intelligent magnetic nano-composite using amphiphilic compound and tissue-specific binding substances, and contrast agent comprising the same | |
Asik et al. | One step emission tunable synthesis of PEG coated Ag 2 S NIR quantum dots and the development of receptor targeted drug delivery vehicles thereof | |
Kritchenkov et al. | Functionalized Pt (II) and Ir (III) NIR emitters and their covalent conjugates with polymer-based nanocarriers | |
Fahmi et al. | Development of bovine serum albumin-modified hybrid nanoclusters for magnetofluorescence imaging and drug delivery | |
Tudisco et al. | Comparison between folic acid and gH625 peptide-based functionalization of Fe 3 O 4 magnetic nanoparticles for enhanced cell internalization | |
Alea-Reyes et al. | Nanostructured materials for photodynamic therapy: synthesis, characterization and in vitro activity | |
Xian et al. | Functionalization of luminescent lanthanide complexes for biomedical applications | |
KR101201473B1 (en) | Preparation method of self assembling drug and cell delivery system, and self assembling drug and cell delivery system prepraed therefrom | |
Fahmi et al. | Potential application of oleylamine-encapsulated AgInS2-ZnS quantum dots for cancer cell labeling | |
EP2490672A2 (en) | Modular functional peptides for the intracellular delivery of nanoparticles | |
Chakrabortty et al. | NIR-emitting and photo-thermal active nanogold as mitochondria-specific probes | |
Ren et al. | PEGylated β-NaGdF4/Tb@ CaF2 core/shell nanophosphors for enhanced radioluminescence and folate receptor targeting |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FEPP | Fee payment procedure |
Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
AS | Assignment |
Owner name: NATIONAL TECHNOLOGY & ENGINEERING SOLUTIONS OF SANDIA, LLC, NEW MEXICO Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SAVA GALLIS, DORINA F.;BUTLER, KIMBERLY;SIGNING DATES FROM 20210702 TO 20210711;REEL/FRAME:056820/0363 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
AS | Assignment |
Owner name: U.S. DEPARTMENT OF ENERGY, DISTRICT OF COLUMBIA Free format text: CONFIRMATORY LICENSE;ASSIGNOR:NATIONAL TECHNOLOGY & ENGINEERING SOLUTIONS OF SANDIA, LLC;REEL/FRAME:059775/0659 Effective date: 20210630 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
AS | Assignment |
Owner name: U.S. DEPARTMENT OF ENERGY, DISTRICT OF COLUMBIA Free format text: CONFIRMATORY LICENSE;ASSIGNOR:NATIONAL TECHNOLOGY & ENGINEERING SOLUTIONS OF SANDIA, LLC;REEL/FRAME:059995/0362 Effective date: 20210630 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |